JPH089595B2 - Method for producing 2-hydroxypyridine - Google Patents
Method for producing 2-hydroxypyridineInfo
- Publication number
- JPH089595B2 JPH089595B2 JP1106105A JP10610589A JPH089595B2 JP H089595 B2 JPH089595 B2 JP H089595B2 JP 1106105 A JP1106105 A JP 1106105A JP 10610589 A JP10610589 A JP 10610589A JP H089595 B2 JPH089595 B2 JP H089595B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- chloropyridine
- hydroxypyridine
- amount
- aqueous alkaline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 8
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003518 caustics Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Description
【発明の詳細な説明】 本発明は２−ヒドロキシピリジン又は２−（1H）−ピ
リジンの新規製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 2-hydroxypyridine or 2- (1H) -pyridine.
この化合物は医薬、たとえばペニシリン及びセファロ
スポリン誘導体の製造に於いて重要な中間体として使用
される。This compound is used as an important intermediate in the preparation of pharmaceuticals such as penicillin and cephalosporin derivatives.
これは米国特許第1,778,874号明細書に従って２−ク
ロルピリジンを濃塩酸中で150℃で加圧下に加水分解し
て製造される。この著しい反応条件にもかかわらず数時
間の反応で24％の収率しか得られない。その改良として
J.Chem.Soc.,B（1968）,492によれば２−クロルピリジ
ンとカリウムエチラートとを反応させ、次いで形成され
た２−メトキシピリジンを酸性水性溶液中で加水分解す
ることが行われている。それによれば70％まで収率の上
昇が得られるが、反応は２段階工程で行われる。It is prepared according to US Pat. No. 1,778,874 by hydrolyzing 2-chloropyridine in concentrated hydrochloric acid at 150 ° C. under pressure. Despite these striking reaction conditions, only 24% yield is obtained in a few hours of reaction. As an improvement
According to J. Chem. Soc., B (1968), 492, 2-chloropyridine is reacted with potassium ethylate, and then the 2-methoxypyridine formed is hydrolyzed in an acidic aqueous solution. ing. Although it gives an increase in yield of up to 70%, the reaction is carried out in a two-step process.
したがってこの反応工程を簡略化し、２−ヒドロキシ
ピリジンの収率を増加させることが課題である。Therefore, it is a subject to simplify this reaction process and to increase the yield of 2-hydroxypyridine.
この課題の解決は、請求項１−５に記載した方法によ
って行われる。This problem is solved by the method described in claims 1-5.
本発明者は、２−クロルピリジンを第三アルコールの
存在下にアルカリ性水性溶液と反応させた場合、２−ヒ
ドロキシピリジンを２−クロルピリジンから一段階反応
で高純度でかつ良好な収率で製造することができること
を見い出した。The present inventor produced 2-hydroxypyridine from 2-chloropyridine in a one-step reaction with high purity and good yield when 2-chloropyridine was reacted with an alkaline aqueous solution in the presence of a tertiary alcohol. I have found what I can do.
第三アルコールが存在しないと濃苛性カリ溶液と煮沸
しても対応する反応が全く行われないことは驚くべきこ
とである。It is surprising that in the absence of tertiary alcohol, boiling the concentrated potash solution does not cause any corresponding reaction.
第三アルコールとして反応条件（80−120℃）下で液
状であるすべての第三アルコールを使用することができ
る。特に第三ブチル−及びアミルアルコールが適する。
使用される第三アルコールの量は、使用される水性アル
カリ性溶液の0.5−５倍量の範囲にある。As tertiary alcohol it is possible to use all tertiary alcohols which are liquid under the reaction conditions (80-120 ° C.). Especially tert-butyl and amyl alcohol are suitable.
The amount of tertiary alcohol used is in the range of 0.5-5 times the amount of aqueous alkaline solution used.
アルカリ性、水性溶液は水酸化アルカリ、アンモニ
ア、第一、第二又は第三アルキルアミンの又はアルカリ
土類の水酸化物の水性溶液である。この際本発明による
反応がますます良好に進行すると、溶液はより一層アル
カリ性になる。したがって濃アルカリ溶液、特に苛性カ
リ溶液が好ましいアルカリ性水性溶液である。Alkaline, aqueous solutions are aqueous solutions of alkali hydroxides, ammonia, primary, secondary or tertiary alkylamine or alkaline earth hydroxides. The better the reaction according to the invention proceeds, the more alkaline the solution becomes. Therefore, concentrated alkaline solutions, especially caustic potash solutions, are preferred alkaline aqueous solutions.
アルカリ量は、塩素の分解及びクロリドとして中和し
た後にまだ反応媒体の明白なアルカリ性反応を生じる様
に調節されねばならない。クロルピリジンに対して1.5
〜３倍等モル量のアルカリ性物質を使用するのが好まし
い。The amount of alkali must be adjusted so that after decomposition of chlorine and neutralization as chloride, a still alkaline reaction of the reaction medium still takes place. 1.5 for chloropyridine
It is preferred to use ~ 3 times equimolar amounts of alkaline material.
本発明による反応は、高められた温度で、好ましくは
反応混合物の沸騰範囲の温度で行われる。したがって反
応混合物を、好ましくは還流下に大気圧で加熱する。設
備のととのった装置が与えられた場合、反応を高められ
た圧力かつ高められた温度でも行うことができる。The reaction according to the invention is carried out at elevated temperature, preferably in the boiling range of the reaction mixture. Therefore, the reaction mixture is heated at atmospheric pressure, preferably under reflux. The reaction can also be carried out at elevated pressure and elevated temperature, given a well-equipped facility.
反応を行った後に、反応混合物を公知の方法で後処理
する。第三アルコールを回収し、過剰の苛性アルカリ溶
液を中和し、形成された塩から所望の２−ヒドロキシピ
リジンを分離する。After carrying out the reaction, the reaction mixture is worked up in a known manner. The tertiary alcohol is recovered, the excess caustic solution is neutralized and the desired 2-hydroxypyridine is separated from the salt formed.
本発明を次の例によって詳述する： 例 ｔ−アミルアルコール600ml及び水酸化カリウム（約9
0％）330g（約5.3モル）から成る混合物を還流加熱（11
8℃）する。次いで1.5時間以内で２−クロルピリジン22
7g（２モル）を滴下し（底部温度は118℃から105℃に下
がる。）、24時間還流煮沸する。The invention is illustrated by the following example: Example t-amyl alcohol 600 ml and potassium hydroxide (about 9
A mixture of 330 g (about 5.3 mol) (0%) is heated under reflux (11
8 ℃). 2-chloropyridine 22 within 1.5 hours
7 g (2 mol) is added dropwise (bottom temperature drops from 118 ° C to 105 ° C), and the mixture is boiled under reflux for 24 hours.
その後ｔ−アミルアルコールを留去する。次いで水10
00mlを加え、残留物が冷たい状態でまだ撹拌できる限り
再び蒸留する（約600ml留出）。Then t-amyl alcohol is distilled off. Then water 10
Add 00 ml and distill again as long as the residue is still cold and can be stirred (about 600 ml distillate).
混合物を冷却し、冷却下に濃HC1約340mlでpH5−６に
調整し、残りの水を留去する。残留物を60℃に冷却し、
徐々にメタノール700mlを加え、再び室温まで冷却し、
沈殿した無機塩を吸引取し、数回メタノール100mlで
洗滌する。The mixture is cooled, adjusted to pH 5-6 with about 340 ml concentrated HC1 under cooling and the remaining water is distilled off. Cool the residue to 60 ° C,
Slowly add 700 ml of methanol, cool to room temperature again,
The precipitated inorganic salt is suctioned off and washed several times with 100 ml of methanol.
一緒にされたメタノール層を蒸発し、残留物を減圧蒸
留する。生成物は174〜178℃/14mmで移行する。The combined methanol layers are evaporated and the residue is distilled under reduced pressure. The product migrates at 174-178 ° C / 14 mm.
収量:176.5g＝理論値の92％ 含有率:99.7％Yield: 176.5g = 92% of theoretical content: 99.7%
───────────────────────────────────────────────────── フロントページの続き (72)発明者 ウオルフガング・ウアイッス ドイツ連邦共和国、ネッカールハウゼン、 ケルテルウエーク、３ (72)発明者 ハンス・ウエルネル・クレフネル ドイツ連邦共和国、バッテンベルク、パノ ラマストラーセ、13 (56)参考文献 特開 昭64−75468（ＪＰ，Ａ) 米国特許3355456（ＵＳ，Ａ) ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Wolfgang Weiss, Federal Republic of Germany, Neckalhausen, Kertelwake, 3 (72) Inventor Hans Wernel Clefner, Federal Republic of Germany, Battenberg, Panoramastraße, 13 ( 56) References Japanese Patent Laid-Open No. 64-75468 (JP, A) US Patent 3355456 (US, A)
Claims (5)
在下に水性アルカリ性溶液と反応させることを特徴とす
る２−クロルピリジンから２−ヒドロキシピリジンを製
造する方法。1. A method for producing 2-hydroxypyridine from 2-chloropyridine, which comprises reacting 2-chloropyridine with an aqueous alkaline solution in the presence of a tertiary alcohol.
溶液を使用する請求項１記載の方法。2. The method according to claim 1, wherein a concentrated caustic solution is used as the aqueous alkaline solution.
倍等モル量を使用する請求項１又は２記載の方法。3. Alkali 1.5 to 3 relative to chloropyridine
The method according to claim 1 or 2, wherein a double equimolar amount is used.
に実施する請求項１ないし３のいずれかに記載した方
法。4. A process according to claim 1, wherein the reaction is carried out at atmospheric pressure and at the temperature of the boiling point of the reaction mixture.
カリ性溶液の0.5〜５倍量の範囲にある請求項１ないし
４のいずれかに記載した方法。5. The process according to claim 1, wherein the amount of tertiary alcohol used is in the range of 0.5 to 5 times the amount of the aqueous alkaline solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3814358.5 | 1988-04-28 | ||
| DE3814358A DE3814358A1 (en) | 1988-04-28 | 1988-04-28 | METHOD FOR PRODUCING 2-HYDROXYPYRIDINE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01313462A JPH01313462A (en) | 1989-12-18 |
| JPH089595B2 true JPH089595B2 (en) | 1996-01-31 |
Family
ID=6353094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1106105A Expired - Fee Related JPH089595B2 (en) | 1988-04-28 | 1989-04-27 | Method for producing 2-hydroxypyridine |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US4942239A (en) |
| JP (1) | JPH089595B2 (en) |
| DE (1) | DE3814358A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9704795D0 (en) * | 1997-03-07 | 1997-04-23 | Zeneca Ltd | Chemical process |
| GB9819235D0 (en) * | 1998-09-03 | 1998-10-28 | Zeneca Ltd | Chemical process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3355456A (en) | 1965-05-06 | 1967-11-28 | Dow Chemical Co | Production of monohalopyridinols |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1778784A (en) * | 1930-10-21 | Gesellschaft | ||
| DE406208C (en) * | 1922-08-16 | 1924-11-15 | A E Tschitschibabin Dr | Process for preparing oxy derivatives of pyridine, quinoline, their homologues and other bases containing pyridine nuclei |
-
1988
- 1988-04-28 DE DE3814358A patent/DE3814358A1/en not_active Ceased
-
1989
- 1989-03-01 US US07/317,537 patent/US4942239A/en not_active Expired - Lifetime
- 1989-04-27 JP JP1106105A patent/JPH089595B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3355456A (en) | 1965-05-06 | 1967-11-28 | Dow Chemical Co | Production of monohalopyridinols |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01313462A (en) | 1989-12-18 |
| DE3814358A1 (en) | 1989-11-09 |
| US4942239A (en) | 1990-07-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |